The present invention relates to a process for producing an alkanediol derivative.
Alkanediol derivatives represented by the following general formula (II): 
and, in particular, optically active (R)xe2x80x94 or (S)-alkanediol derivatives are useful as a building block for agrochemical or pharmaceutical. For obtaining such a derivative, there has been known a process which comprises reducing a hydroxy carboxylic acid ester (e.g. an optically active 2-hydroxypropanoate or an optically active 3-hydroxybutanoate) or a compound obtained by protecting the hydroxyl group of the above ester with dihydropyran or the like, using lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride.
The above lithium aluminum hydride and sodium bis(2-methoxyethoxy)aluminum hydride, however, are difficult to handle in a large amount industrially from the safety standpoint. Therefore, active investigations have been made on a process for conducting the above-mentioned reduction using sodium borohydride which is easy to handle industrially.
However, it is generally impossible to reduce ester group to alcohol group using sodium borohydride [Tetrahedron, Vol.35, p.567 (1979)]. Hence, various reaction conditions have long been studied. For example, there were proposed a process which comprises conducting the reaction in the presence of a Lewis acid (e.g. aluminum chloride) [J. Am. Chem. Soc., Vol.78, p.2582 (1956)] and a process which comprises conducting the reaction in the presence of a metal salt (e.g. lithium chloride, lithium bromide or potassium bromide) [J. Am. Chem. Soc., Vol.77, p.6209 (1955)].
There were also proposed a process which comprises suspending sodium borohydride in tetrahydrofuran or tertiary butyl alcohol and slowly adding thereto a primary alcohol (e.g. methanol) under refluxing [Bull. Chem. Soc. Jpn., Vol.57, p.1948 (1984)], a process using a mixed solvent of an ether type solvent and a primary alcohol [Synlett., p.1636 (1999): WO 98/8793], a process using a polyethylene glycol as a solvent (JP-A-10-507996), a process using a mixed solvent of 1,2-dichloroethane and methanol (JP-A-1-250369), etc.
However, in obtaining an alkanediol derivative represented by the above general formula (II) by conducting reduction according to any of the above known processes, there are various problems. That is, for example, in the processes using a Lewis acid or a metal salt, the Lewis acid or the metal salt added results in an increase in the amount of waste material, which is not preferred; and in the process of dropwise adding a primary alcohol under refluxing, a large amount of hydrogen is generated rapidly when the process is carried out on a large scale, which is dangerous. In view of that solvent recovery is necessary in an industrial application of the above processes using a solvent, the process using an ether type solvent has a problem of requiring special facilities for ether separation from alcohol as well as for security against peroxide, and the use of 1,2-dichloroethane is restricted for its ozone depletion and global warming.
Thus, in the technical field to which the present invention belongs, no proposal has been made on a process for producing an alkanediol derivative represented by the general formula (II) safely without giving rise to racemization, and development of such a process has been desired.
The present invention aims at solving the above-mentioned problems and providing a novel and efficient process for producing an (R)xe2x80x94, (S)xe2x80x94 or (RS)-alkanediol derivative which is useful as a building block.
In order to achieve the above aim, the present inventors made a study on a process for producing an alkanediol derivative represented by the general formula (II) by reducing a corresponding ester compound with sodium borohydride. As a result, it was found out surprisingly that the above ester compound is reduced with sodium borohydride at room temperature in a mixed solvent of a non-polar aprotic solvent, i.e. an aromatic hydrocarbon (e.g. chlorobenzene or toluene), an aliphatic hydrocarbon (e.g. hexane or heptane), an alicyclic hydrocarbon (e.g. cyclohexane or methylcyclohexane) or the like and a primary alcohol (e.g. methanol or ethanol) and is converted to an alkanediol derivative of the general formula (II) at a high yield without giving rise to racemization when the ester compound is optically active. The present invention has been completed based on the above finding. Incidentally, that the ester group of the ester compound is reduced to an alcohol with sodium borohydride at room temperature in a non-polar solvent with an addition of a primary alcohol, is an entirely novel finding which is far beyond the anticipation of those skilled in the art.
The present invention is described in detail below.
The present invention provides the following inventions [1] and [2].
[1] A process for producing an alcohol derivative represented by the following general formula (II): 
(wherein R2 and R3 are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; X is a hydrogen atom or a protecting group for hydroxyl group; and n is 0 or 1), which process comprises reducing an ester compound represented by the following general formula (I): 
(wherein R1 is an alkyl group having 1 to 4 carbon atoms; and R2, R3, X and n have the same definitions as given above) with sodium borohydride in a mixed solvent of at least one kind of solvent selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons and alicyclic hydrocarbons and a primary alcohol.
[2] A process according to the above [1], wherein the primary alcohol is methanol.
First, description is made on the ester compound represented by the general formula (I) which is used as a raw material in the present invention.
In the ester compound represented by the general formula (I) which is used as a raw material in the present process, the substituent represented by R1 in the general formula (I) is an alkyl group having 1 to 4 carbon atoms, exemplified by methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and isobutyl group; and the substituents represented by R2 and R3 are each independently a hydrogen atom or, similarly to R1, an alkyl group having 1 to 4 carbon atoms.
The substituent represented by X in the general formula (I) is a hydrogen atom or a protecting group for hydroxyl group; and n is 0 or 1, indicating that the ester compound represented by the general formula (I) includes a compound wherein hydroxyl group is adjacent to carboxyl group and a compound wherein a carbon atom is present between hydroxyl group and carboxyl group.
Accordingly, as the ester compound represented by the general formula (I) wherein the substituent represented by X is a hydrogen atom, there can be mentioned, for example, methyl (R)-lactate, ethyl (R)-lactate, isobutyl (R)-lactate, methyl (S)-lactate, ethyl (S)-lactate, methyl (R)-3-hydroxybutanoate, methyl (S)-3-hydroxybutanoate and methyl (S)-3-hydroxy-2-methylpropionate or the like.
As the ester compound represented by the general formula (I) wherein the substituent represented by X is a protecting group for hydroxyl group, there can be mentioned, for example, compounds obtained by protecting the hydroxyl group of a compound represented by the general formula (I) wherein the substituent represented by X is a hydrogen atom, such as methyl (R)-lactate, ethyl (R)-lactate, isobutyl (R)-lactate, methyl (S)-lactate, ethyl (S)-lactate, methyl (R)-3-hydroxybutanoate, methyl (S)-3-hydroxybutanoate, methyl (S)-3-hydroxy-2-methylpropionate or the like, according to a conventional method.
The protecting group for hydroxyl group, used in the present invention is preferably a group which can be removed under an acidic condition, such as substituted methyl group, substituted ethyl group or the like. The substituted methyl group can be exemplified by methoxymethyl group (MOM) and 2-methoxyethoxymethyl (MEM) group, and the substituted ethyl group can be exemplified by tetrahydropyranyl group and (C1-6 alkoxy)ethyl groups such as 1-ethoxyethyl group, 1-isobutoxyethyl group and the like.
The use of these protecting groups is described in detail in xe2x80x9cProtective Groups in Organic Synthesis-3rd Edition, John Wiley and Sons, Inc. (1999)xe2x80x9d. In the present invention, by protecting hydroxyl group according to a conventional method described in the above literature, it is possible to obtain an ester compound represented by the general formula (I) wherein the substituent represented by X is a protecting group for hydroxyl group; it is also possible to remove, as necessary, the protecting group for hydroxyl group.
For example, a compound represented by the general formula (I) wherein the substituent represented by X is a substituted ethyl group, can be obtained by reacting a compound represented by the general formula (I) wherein the substituent represented by X is a hydrogen atom, with an alkyl vinyl ether in a solvent-free state or in an appropriate solvent in the presence of an acid catalyst.
The alkyl vinyl ether can be exemplified by dihydropyran, ethyl vinyl ether, propyl vinyl ether, isobutyl vinyl ether and cyclohexyl vinyl ether. These compounds are on the market and also available industrially.
As the acid catalyst, there are used organic acids such as camphorsulfonic acid, para-toluenesulfonic acid, trifluoroacetic acid and the like; inorganic acids such as sulfuric acid, hydrogen chloride and the like; pyridinium para-toluenesulfonate; phosphorous oxychloride; and so forth. The amount of the acid catalyst used is not critical but is 0.5 to 10 mole %, preferably 1 to 3 mole % relative to the compound represented by the general formula (I) wherein the substituent represented by X is a hydrogen atom.
As the solvent which may be used in the reaction for protection of hydroxyl group, there can be used any solvent which can dissolve the compound represented by the general formula (I) wherein the substituent represented by X is a hydrogen atom but does not react with the compound represented by the general formula (I) wherein the substituent represented by X is a hydrogen atom. There can be preferably mentioned, for example, aromatic, aliphatic or alicyclic hydrocarbon solvents such as toluene, xylene, cyclohexane, methylcyclohexane, octane, heptane and the like. The amount of the solvent used is not restricted but is 0.3 to 2.0 liters, preferably 0.5 to 1.5 liters per mole of the compound represented by the general formula (I) wherein the substituent represented by X is a hydrogen atom.
Next, description is made on the process of the present invention wherein an ester compound represented by the general formula (I) is reduced to an alkanediol derivative represented by the general formula (II).
The reaction of the present process can be conducted simply by mixing an ester compound represented by the general formula (I), sodium borohydride and a solvent and stirring the resulting mixture. There is no particular restriction as to the addition order of these substances.
The solvent used in the above reaction is a mixed solvent of at least one kind selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons and alicyclic hydrocarbons and a primary alcohol.
As the aromatic hydrocarbons, there can be mentioned, for example, chlorobenzene, toluene, 4-chlorotoluene, 2-chlorotoluene, 2,4-dichlorotoluene, naphthalene and 1-chloronaphthalene; as the aliphatic hydrocarbons, there can be mentioned, for example, pentane, hexane, heptane, octane and isooctane; and as the alicyclic hydrocarbons, there can be mentioned, for example, cyclohexane and methylcyclohexane.
The solvent selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons and alicyclic hydrocarbons can be one kind or two or more kinds (in this case, there is no particular restriction as to their mixing proportions). The amount of the solvent used is not particularly restricted and is 0.3 to 2.0 liters, preferably 0.5 to 1.5 liters per mole of the ester compound represented by the general formula (I).
As the primary alcohol to be mixed with the above hydrocarbon solvent to constitute a mixed solvent used in the above-mentioned reaction, there can be mentioned, for example, methanol and ethanol. Methanol is preferred for the high reaction rate. The primary alcohol is used in an amount of 3 to 12 equivalents, preferably 5 to 8 equivalents relative to the ester compound represented by the general formula (I); however, the amount used is not restricted thereto.
Meanwhile, the amount of sodium borohydride used is 1 to 6 equivalents, preferably 1 to 3 equivalents, more preferably 1.3 to 2.0 equivalents relative to the ester compound represented by the general formula (I); however, the amount used is not restricted thereto.
The above reaction proceeds smoothly at a reaction temperature of 0 to 80xc2x0 C., preferably 20 to 40xc2x0 C. and, in particular, stirring at room temperature is simple and gives a high yield.
In the reaction of the present process, there can be employed various specific procedures; for example, a procedure in which an ester compound represented by the general formula (I) and sodium borohydride are suspended or dissolved in toluene, methanol is added dropwise thereto at room temperature, and, in this state, stirring is conducted up to the completion of a reaction, or a procedure in which a methanol solution of an ester compound represented by the general formula (I) is added at room temperature to a toluene suspension of sodium borohydride.
After the completion of the reaction, the reaction product is isolated by an ordinary extraction operation and purified by distillation, or water is added to the reaction mixture to remove the alcohol so that the reaction product dissolved in toluene can be used per se in the next reaction.
Of the ester compounds represented by the general formula (I), the alkoxyethyl group-protected (R)xe2x80x94 or (S)-propionic acid esters represented by the following general formula (III), excluding some compounds, are not described in Chemical Abstract and are novel compounds whose properties are unknown. 
[wherein X1 is a (C1-6 alkoxy)ethyl group, and R has the same definition as the above-mentioned R1].
As such novel (C1-6 alkoxy)ethyl group-protected (R)xe2x80x94 or (S)-propionic acid esters represented by the general formula (III), there can be specifically mentioned, for example, isobutyl (R)-2-(1-ethoxyethoxy)propionate, isobutyl (R)-2-(1-isobutoxyethoxy)propionate, methyl (R)-2-(1-isobutoxyethoxy)propionate, isobutyl (R)-2-(1-n-butoxyethoxy)propionate and isobutyl (R)-2-(1-cyclohexyloxyethoxy)propionate.
The alkoxyethyl group used as a protecting group for hydroxyl group in the compound represented by the general formula (III), as compared with tetrahydropyranyl group, is removable under milder conditions and therefore is known to hardly cause racemization in the reaction for protecting group removal in optically active compound. In, for example, S. Chladek and J. Smrt., Chem. and Ind. (London), 1719 (1964), it is described that while racemization takes place partially in the removal of tetrahydropyranyl group, no racemization takes place in the removal of ethoxyethyl group.
Of the alkanediol derivatives represented by the general formula (II), the 1,2-propanediol derivatives represented by the following general formula (IV), other than some compounds, are novel compounds not described in Chemical Abstract. 
(wherein X1 has the same definition as given above)
As such novel 1,2-propanediol derivatives represented by the general formula (IV), there can be specifically mentioned, for example, (R)-2-(1-isobutoxyethoxy)-1-propanol, (S)-2-(1-isobutoxyethoxy)-1-propanol, (R)-2-(1-n-butoxyethoxy)-1-propanol and (R)-2-(1-cyclohexyloxyethoxy)-1-propanol.